In many drug delivery applications a strict control of the particle size and particle size distribution is required. An example is the delivery of drug-releasing particles from a catheter, more particularly where delivery into the capillary bed of a tumour such as a liver tumour is required. In this application of drug delivery, the particles are supposed to embolise in the smallest capillaries from where they can release drugs, such as cytostatics or provide local β or γ radiation. This is the case for particles loaded with Holmium acetyl-acetonate. The size of the particles plays an important role in the efficacy of the treatment. If the particles are too small, they will circulate and accumulate in other areas, for instance the lungs. If they are too big, they will not reach the smallest capillaries. Therefore the most effective therapy will be achieved with precisely and uniformly tailored particles.
One way to arrive at very well-defined particles derived from biodegradable polymers is to use a technique in which a liquid with the dissolved polymer and the drug is pushed through a capillary whereby the liquid jet is broken up into droplets, for instance by application of a frequency from a piezo-element or similar devices. Such systems have been described in U.S. Pat. No. 6,669,916, U.S. Pat. No. 6,998,074 and WO2006/003581 and Berkland et al. (2001) J. Control. Release 73, 59-74. In U.S. Pat. No. 6,669,916 the jetting is accompanied by an additional downward force or acceleration to make it possible to produce droplets that are smaller than the nozzle diameter. An example of such a downward force is a co-flowing stream of a solution of polyvinylalcohol. A problem noted in U.S. Pat. No. 6,669,961 is the generation of particles from nozzles that are smaller than 30 μm in diameter, which get clogged easily. The technology disclosed in U.S. Pat. No. 6,669,961 allows the use of fairly concentrated solutions (5% of polymer) for the production of particles in the desired size range. However, because of the additional force that is needed, the production system becomes more complicated. Moreover for particles significantly smaller than 50 μm the size distributions are wider than for particle above 50 μm. A similar carrier stream, intended to encapsulate for instance an aqueous phase, rather than splitting up the stream in smaller droplets has been disclosed in U.S. Pat. No. 6,599,627. This technique generates relatively large capsules, i.e. larger than 100 μm.
Particles with a size of 65 μm have been produced using drop-on-demand nozzles of 65 μm as described by Radulescu et al. (2003, Proc. 11th Int. Symp. Control. Rel. Soc). Herein, an assistant pressure can be applied to enhance the production speed. U.S. Pat. No. 6,998,074, from the same research group, describes the use of a drop-on-demand ink-jet method without assistant pressure, with a nozzle submerged in a liquid to fabricate polymer microspheres.
WO2006/003581 describes that smaller particles than those known in the art can be produced using a submerged nozzle to which a frequency is applied, preferably in combination with an assistant pressure. Careful shrinkage of the jetted emulsion droplets yielded particles as small as 2 μm. Monodisperse hollow capsules could be obtained as also described in Böhmer et al. (2006) (Colloids and Surfaces 289, 96-104). In the described system, an assistant pressure not only allows higher jetting rates but also prevents clogging of the nozzle of the device. If no additional pressure is used, polymers such as poly-lactic acid, will precipitate at the interface between the fluid to be jetted and the continuous phase. The process is described in WO2006/003581 uses lower polymer concentration than the process described in U.S. Pat. No. 6,669,961 or U.S. Pat. No. 6,767,637, resulting in the shrinkage of the emulsion droplets to smaller sizes.
All methods described in the prior art documents cited above make use of additives such as polyvinylalcohol to stabilize the emulsion droplets and the resulting particles. The addition of polyvinylalcohol has two effects on the preparation of polymer particles from biodegradable polymers. It stabilises both the emulsion droplets and the particles formed therefrom.
Besides issues of size and uniformity, another problem in inkjetting particles is the fragility of emulsion droplets in the receiving fluid. Stirring during solvent extraction has to occur very gently, otherwise the droplets break-up easily. Böhmer et al. (2006) Colloids & Surfaces, Physicochem. Eng. Aspects 289, 96-104 describes a system wherein microparticles are not stirred after release from a nozzle.